Theoretical study for investigating three experimental dose-response curves of rosy odorants on human olfactory receptor OR2A25 via molecular docking calculations and statistical physics modeling.

Humans perceived rosy odorants, as well as other odorant molecules, through olfactory receptors that belong to the family of seven-transmembrane GPCRs. However, characterizing olfactory receptors remains a major challenge, largely due to the lack of X-ray crystallographic structures with high resolution. In this work, a theoretical statistical physics simulation and analysis, validated with molecular docking calculations, was applied to obtain deeper insight into human olfactory perception function by reducing the docking process to an adsorption one. Fitting results showed that human OR2A25 responded selectively to rosy odorants such as phenyl alcohol, geraniol, and citronellol. From a microscopic perspective, an advanced statistical physics characterization, based on a monolayer model with one adsorption energy (MM1E), provided a high degree of precision in characterizing and understanding the docking mechanism that cannot be obtained by experimental methods. Indeed, docking simulations revealed that the adsorption process involves binding energies 12.13 kJ/mol for phenyl alcohol-OR2A25, 10.04 kJ/mol for geraniol-OR2A25, and 8.78 kJ/mol for citronellol-OR2A25. Thus, these docking energy values obtained by molecular docking simulation were found to be slightly close to molar adsorption energies obtained by statistical physics modeling. From a macroscopic perspective, four thermodynamic functions, governing the mechanism of adsorption, were examined. The evolution of disorder during the proposed adsorption process was assessed through analysis of the configurational entropy. Moreover, the adsorption process involved in the three tested olfactory systems was found to be exothermic and spontaneous, as indicated by the values of the internal energy, enthalpy, and Gibbs free energy.